This is a revised collaborative R01 proposal to study the genetics of cocaine dependence (CD) and related phenotypes, using a multifaceted approach. An important genetic contribution to risk for CD and related phenotypes is supported by clinical genetic data and by our first round of linkage results. The major purpose of this proposal is to identify specific risk alleles at loci predisposing to CD and related traits. The goals are to collect a set of >2000 CD cases and >2000 carefully ascertained population controls, and to recruit additional small nuclear families (SNFs) through affected cases, when possible. The resulting sample based on CD affection will have sufficient power to identify linkage disequilibrium with trait under reasonable assumptions of genetic heterogeneity. The clinical work will take place at five university-based programs in CT (Univ. of CT and Yale Univ.), MD (Johns Hopkins Univ.), PA (Univ. of PA), and SC (Medical Univ. of SC), and the laboratory and statistical work will be performed at Yale, Boston Univ. School of Medicine, and the Southwest Foundation for Biomedical Research. Affection will be defined according to DSM-IV diagnostic criteria, ascertained using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). This computerized instrument was developed in the previous grant period and has been shown to yield reliable diagnoses. We have implemented an extensive program to assure the quality of the detailed set of clinical data collected. This will continue the first large-scale study of CD gene mapping. Results from the first iteration of the project, in terms of subject recruitment and characterization and data analysis, support our ability to complete this ambitious research program successfully. This research program will also create an extensive resource for use by future investigators. The project will build on the successes of the first five-year SNF gene mapping project led by Drs. Gelernter and Kranzler (which has already identified several genomic "regions of interest" for cocaine-related traits). The project will also contribute to a substantial increase in our understanding of the mechanisms of CD, and may lead to new approaches to the prevention and treatment of this pervasive societal problem. Public Health Relevance: This study will help to identify specific gene variants that contribute to the risk of cocaine and other drug dependence. Knowledge of the gene variants will help to identify people at greatest risk of developing the disorder, thereby improving prevention efforts.